Sarcopenia represents a major clinical and societal challenge facing rapidly aging populations. Accessible and specific biomarkers represent valuable tools, both in diagnosis and assessing the efficacy of therapeutic interventions.

C-terminal agrin fragment (CAF) is the most commonly used blood-based biomarker of neuromuscular junction degradation in aging, inactivity and disease, but large unexplained interindividual variation exists, limiting its diagnostic and prognostic value. Exercise and medication may explain some of this variation.

The aim of this study was to investigate the influence of a single bout (1EX) or 48 bouts (48EX) of heavy resistance exercise (EX), with or without angiotensin II type I receptor blocker (losartan (LOS)) supplementation, on serum CAF levels in healthy older men. Eighty-three healthy, normotensive older men were enrolled in one of two randomized placebo (PLA) controlled trials. 1EX: 25 participants (EX ± LOS), with a mean age of 70 ± 7 years, had blood drawn before and after (4.5 h, Days 1, 4 and 7) a single bout of unilateral heavy resistance exercise of the quadriceps muscles. 48EX: at baseline, and after 8 and 16 weeks of a progressive heavy resistance exercise program, 58 participants (LOS-EX, n = 20; LOS-SED, n = 20; PLA-EX, n = 18), with a mean age of 72 ± 5 years, had blood drawn, and specific force (strength per unit mass) was measured by dynamometer and magnetic resonance imaging of the quadriceps muscles.

Serum CAF was measured by ELISA. At baseline, CAF showed weak correlations with age and leg lean mass (both R 2 = 0.07, p < 0.05).

With 48EX, specific force increased in both EX groups (LOS-EX + PLA-EX) by 13%-14% at 8 weeks and 14%-17% at 16 weeks (p < 0.0001), with no change in LOS-SED (p > 0.05), confirming the efficacy of the 48EX program. Serum CAF increased in LOS-EX and LOS-SED by 4%-7% at 8 weeks and 7%-9% at 16 weeks (p < 0.005) respectively, with no change in PLA-EX (p > 0.05). 1EX reduced CAF by 8% 1 day postexercise (p < 0.05), with no correlation to circulating creatine kinase levels (p > 0.05), a marker of muscle damage.

Serum CAF was unaffected by 16 weeks of EX but increased by LOS supplementation. 1EX, performed with one leg, acutely lowered serum CAF, albeit with substantial interindividual variability. These findings collectively identify novel stimuli of serum CAF turnover-drug interaction and time from last exercise bout to blood sampling.

These findings add value to CAF as a neuromuscular biomarker and highlight important experimental design aspects for future clinical studies.